Origins of High-Activity Cage-Catalyzed Michael Addition

Cage catalysis continues to create significant interest, yet catalyst function remains poorly understood. Herein, we report mechanistic insights into coordination-cage-catalyzed Michael addition using kinetic and computational methods. The study has been enabled by the detection of identifiable catalyst intermediates, which allow the evolution of different cage species to be monitored and modeled alongside reactants and products. The investigations show that the overall acceleration results from two distinct effects. First, the cage reaction shows a thousand-fold increase in the rate constant for the turnover-limiting C–C bond-forming step compared to a reference state. Computational modeling and experimental analysis of activation parameters indicate that this stems from a significant reduction in entropy, suggesting substrate coencapsulation. Second, the cage markedly acidifies the bound pronucleophile, shifting this equilibrium by up to 6 orders of magnitude. The combination of these two factors results in accelerations up to 109 relative to bulk-phase reference reactions. We also show that the catalyst can fundamentally alter the reaction mechanism, leading to intermediates and products that are not observable outside of the cage. Collectively, the results show that cage catalysis can proceed with very high activity and unique selectivity by harnessing a series of individually weak noncovalent interactions

Kinetics of sulfur-transfer from titanocene (poly)sulfides to sulfenyl chlorides:rapid metal-assisted concerted substitution

The kinetics of sulfur transfer from titanocene (poly)sulfides (RCp2TiS5, Cp2TiS4CMe2, Cp2Ti(SAr)2, Cp2TiCl(SAr)) to sulfenyl chlorides (S2Cl2, RSCl) have been investigated by a combination of stopped-flow UV-Vis/NMR reaction monitoring, titration assays, numerical kinetic modelling and KS-DFT calculations. The reactions are rapid, proceeding to completion over timescales of milliseconds to minutes, via a sequence of two S-S bond-forming steps (k1, k2). The archetypical polysulfides Cp2TiS5 (1a) and Cp2TiS4C(Me2) (2a) react with disulfur dichloride (S2Cl2) through rate-limiting intermolecular S-S bond formation (k1) followed by a rapid intramolecular cyclization (k2, with k2 ≫ k1 [RSCl]). The monofunctional sulfenyl chlorides (RSCl) studied herein react in two intermolecular S-S bond forming steps proceeding at similar rates (k1 ≈ k2). Reactions of titanocene bisthiophenolates, Cp2Ti(SAr)2 (5), with both mono- and di-functional sulfenyl chlorides result in rapid accumulation of the monothiophenolate, Cp2TiCl(SAr) (6) (k1 &gt; k2). Across the range of reactants studied, the rates are relatively insensitive to changes in temperature and in the electronics of the sulfenyl chloride, moderately sensitive to the electronics of the titanocene (poly)sulfide (ρ(Ti-(SAr)) ≈ −2.0), and highly sensitive to the solvent polarity, with non-polar solvents (CS2, CCl4) leading to the slowest rates. The combined sensitivities are the result of a concerted, polarized and late transition state for the rate-limiting S-S bond forming step, accompanied by a large entropic penalty. Each substitution step {[Ti]-SR′ + Cl-SR → [Ti]-Cl + RS-SR′} proceeds via titanium-assisted Cl-S cleavage to generate a transient pentacoordinate complex, Cl-[Cp2TiX]-S(R′)-SR, which then undergoes rapid Ti-S dissociation.</p

Discovery of a small molecule probe that post-translationally stabilizes the survival motor neuron protein for the treatment of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA

Thinking inside the box: mechanisms in non-covalent catalysis with Pd₂L₄ capsules

Non-covalent catalysis with coordination capsules continues to be an ever-expanding subfield of supramolecular chemistry. With this expansion comes increasingly refined studies of reaction mechanism, revealing how non-covalent catalysts reshape the potential energy landscape around the reactants, offering faster reactions, more favourable selectivities, and milder conditions. However, a key methodology that remains underutilised in contemporary mechanistic studies is modelling the kinetics of reaction networks. This thesis describes the effects of a Pd₂L₄ capsule catalyst on the solution phase chemistry of a variety of guests. This is facilitated by monitoring temporal concentrations of multiple species over the duration of catalytic reactions using NMR and UV-visible spectroscopy, and conducting system-level modelling of reaction kinetics to produce new mechanistic insights. Chapter one presents a brief introduction to coordination capsules in general, some examples of their use as non-covalent catalysts, and selected examples of mechanistic study in this subfield. This chapter also introduces various classes of techniques used in mechanistic study, and gives a brief introduction to kinetic modelling methods for catalytic reaction systems. Chapter two concerns the investigation of a catalytic condensation reaction utilising a co-catalyst system of Pd₂L₄ and haloquinone p-fluoranil. Through UV-vis and 1H NMR investigations, the reactivity is proposed to originate from “hidden” Brønsted acid catalysis, initiated by capsule-activated substitution and ionisation chemistry in dichloromethane. Chapter three concerns the investigation of base-catalysed conjugate addition reactions mediated by catalytic Pd₂L₄. Through direct detection of reactive intermediates by ¹H NMR spectroscopy, the kinetics are studied in detail. An origin for the significant degree of rate enhancement is proposed, and the capsule’s ability to efficiently redirect the reaction mechanism is explored. Chapter four concerns a theoretical investigation into the kinetics of product inhibition in bimolecular coupling reactions, catalysed by a generalised coordination capsule. Dual encapsulation mechanisms are shown to be kinetically viable in cases where the binding affinity of the two co-substrates is strongly “biased”. The results presented strongly challenge the conventional belief that non-covalent capsule catalysts are inherently unsuited to promoting net coupling reactions. Chapter five concerns an investigation into the host-guest dynamics of Pd₂L₄-quinone complexes through direct observation of their kinetics using stopped-flow UV-visible spectroscopy. Analysis of the kinetics of binding and exchange processes leads to a more detailed understanding of the chemistry underpinning all catalytic processes using these complexes

SHARPER-DOSY: Sensitivity enhanced diffusion-ordered NMR spectroscopy

Abstract Since its discovery in mid-20th century, the sensitivity of Nuclear Magnetic Resonance (NMR) has increased steadily, in part due to the design of new, sophisticated NMR experiments. Here we report on a liquid-state NMR methodology that significantly increases the sensitivity of diffusion coefficient measurements of pure compounds, allowing to estimate their sizes using a much reduced amount of material. In this method, the diffusion coefficients are being measured by analysing narrow and intense singlets, which are invariant to magnetic field inhomogeneities. The singlets are obtained through signal acquisition embedded in short (<0.5 ms) spin-echo intervals separated by non-selective 180° or 90° pulses, suppressing the chemical shift evolution of resonances and their splitting due to J couplings. The achieved 10−100 sensitivity enhancement results in a 100−10000-fold time saving. Using high field cryoprobe NMR spectrometers, this makes it possible to measure a diffusion coefficient of a medium-size organic molecule in a matter of minutes with as little as a few hundred nanograms of material